CURATOR

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PINBOARD SUMMARY

My research combines principles from physics, engineering, and biology to develop a cure for HIV.

The difficulty of creating a safe and effective vaccine against human immunodeficiency virus (HIV) is stressed by the fact that the first HIV efficacy study to be carried out anywhere in the world in the past seven years is just now taking place in South Africa. While the highest rates of HIV infection occur in South Africa with more than 1,000 people becoming infected each day, HIV is a global epidemic with a clear and urgent need for a solution. The highly mutable nature of HIV is the greatest challenge in developing a vaccine against it; every new virus produced by a cell infected with HIV will vary from the original infecting virus by one amino acid mutation on average. Thus, an effective HIV vaccine will likely need to protect against many diverse strains of the original infecting virus. Recently, antibodies (Abs) that can “broadly-neutralize” a wide range of HIV strains – so-called “bNAbs” – have been isolated from rare AIDS patients. These findings prove that the human immune system can evolve defenses against HIV, and suggest that a rationally designed vaccine and optimum immunization protocol could be successful in treating and preventing HIV infection on a global scale.

Important studies have been performed to study bNAb evolution during natural infection and to design immunization strategies for stimulating this evolution. However, several key questions remain that my research aims to address. Using the tools of statistical mechanics, evolutionary dynamics, and available experimental data, I perform simulations that investigate the mechanisms by which antibodies evolve mutations through a process called affinity maturation (AM) to increase their binding affinity to foreign invaders, and study how this evolution can be directed towards the production of bNAbs against HIV. With a deeper understanding of how AM occurs, we can then leverage this information to design the actual vaccine components (i.e., immunogens) that will most effectively elicit bNAb evolution. In concert with immunogen design, my research aims to determine how best to administer these vaccine components (e.g., as a mixture vs. sequentially) to design an optimum immunization protocol against HIV. If successful, my research will lead to new understanding of the adaptive immune response to different immunization strategies that can be used to guide vaccine design against HIV and other highly mutable pathogens for which there is currently no universal vaccine (e.g., influenza).

Abstract

Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent
vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system
can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags).
Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize
the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the
Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving
bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies,
suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles
that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances
may best promote the evolution of bnAbs.

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